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A Novel CFHR5 Mutation Associated with C3 Glomerulonephritis in a Turkish Girl

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A Novel CFHR5 Mutation Associated with C3 Glomerulonephritis in a Turkish Girl A novel CFHR5 mutation associated with C3 glomerulonephritis in a Turkish girl Nesrin Besbas, Bora Gulhan, Safak Gucer, Emine Korkmaz & Fatih Ozaltin Journal of Nephrology ISSN 1121-8428 Volume 27 Number 4 J Nephrol (2014) 27:457-460 DOI 10.1007/s40620-013-0008-1 1 23 Your article is protected by copyright and all rights are held exclusively by Italian Society of Nephrology. This e-offprint is for personal use only and shall not be self- archived in electronic repositories. If you wish to self-archive your article, please use the accepted manuscript version for posting on your own website. You may further deposit the accepted manuscript version in any repository, provided it is only made publicly available 12 months after official publication or later and provided acknowledgement is given to the original source of publication and a link is inserted to the published article on Springer's website. The link must be accompanied by the following text: "The final publication is available at link.springer.com”. 1 23 Author's personal copy J Nephrol (2014) 27:457–460 DOI 10.1007/s40620-013-0008-1 CASE REPORT A novel CFHR5 mutation associated with C3 glomerulonephritis in a Turkish girl Nesrin Besbas • Bora Gulhan • Safak Gucer • Emine Korkmaz • Fatih Ozaltin Received: 17 July 2013 / Accepted: 31 July 2013 / Published online: 5 December 2013 Ó Italian Society of Nephrology 2013 Abstract C3 glomerulopathy defines a subgroup of syndrome and persistently low C3 level, thus expanding the membranoproliferative glomerulonephritis (MPGN) char- genetic and phenotypic spectrum of the disease. Ecu- acterized by complement 3 (C3)-positive, immunoglobu- lizumab seems to be ineffective in this subtype. lin-negative deposits in immunofluorescence microscopy. It comprises 3 clinical conditions: dense deposit disease, Keywords C3 glomerulopathy Á CFHR5-related C3 glomerulonephritis, and complement factor H-related 5 nephropathy Á CFHR5 mutation Á Hypocomplementemia Á (CFHR5) nephropathy. Mutations in genes encoding reg- Nephrotic syndrome Á Eculizumab ulatory proteins of the alternative complement pathway have been described. A 16-year-old girl was admitted to the hospital due to periorbital edema. Nephrotic syndrome Introduction accompanied by low C3 level was diagnosed. Renal biopsy showed MPGN in light microscopy, only C3 deposits in The term membranoproliferative glomerulonephritis immunofluorescence microscopy, and subendothelial (MPGN) defines a heterogeneous group of kidney diseases electron dense deposits and capillary basement membrane that frequently lead to kidney failure [1]. Histologically, it thickening with double contour formation in electron is characterized by mesangial interposition and the dupli- microscopy. C3 nephritic factor and anti complement fac- cation of glomerular basement membranes that are asso- tor H antibody were negative. Complement factor H level ciated with immune deposits, all of which give an was normal. Genetic screening showed a novel heterozy- appearance of hyperlobulated glomeruli. Recent advances gous p.Cys269Arg variation in the CFHR5 gene without regarding the pathomechanisms of MPGN have led to a any mutation in CFH and CFI genes. Eculizumab therapy more mechanistic classification based on the presence of was started but was unsuccessful at 10 months of follow- immunoglobulins (Igs) and/or complement 3 (C3) deposits up. We have identified a novel heterozygous variation in in immunofluorescence microscopy. In this context, ‘‘C3 CFHR5-related nephropathy presenting with nephrotic glomerulopathy’’ (C3G) has been proposed for those patients with C3(?)Ig(-) MPGNs [2, 3]. Distinct forms of C3G include dense deposit disease (DDD), C3 glomeru- N. Besbas Á B. Gulhan Á F. Ozaltin (&) lonephritis (C3GN), and complement factor H-related 5 Department of Pediatric Nephrology, Hacettepe University (CFHR5) nephropathy. DDD is characterized by intra- Faculty of Medicine, Ankara, Turkey membranous electron dense deposits, in contrast to C3GN e-mail: [email protected] which has subendothelial or, rarely, subepithelial and S. Gucer mesangial electron dense deposits. Acquired and genetic Department of Pediatric Pathology, Hacettepe University defects leading to dysregulation of the alternative pathway Faculty of Medicine, Ankara, Turkey (AP) of the complement system are the underlying patho- genetic mechanism [3]. Common to all C3Gs is the E. Korkmaz Á F. Ozaltin Nephrogenetics Laboratory, Hacettepe University Faculty of uncontrolled activity of AP, which can result from muta- Medicine, Ankara, Turkey tions in genes encoding complement proteins such as CFH, 123 Author's personal copy 458 J Nephrol (2014) 27:457–460 CFI, C3, CFB or acquired antibodies stabilizing C3 con- and lambda light chains (Fig. 1b). Electron microscopy vertase of AP (i.e. C3 nephritic factor) or inhibiting com- showed subendothelial deposits, and capillary basement plement regulators such as anti factor H antibody [4, 5]. membrane thickening with double contour formation CFHR5 (complement factor H-related protein 5) is a regu- (Fig. 1c). Prednisone (45 mg/day) and enalapril (10 mg/ lator of the alternative complement pathway and has been day) were administered. This treatment failed to induce shown to co-localize in the glomerulus with complement remission and low C3 persisted. Therefore, pulse steroid under pathological conditions [6]. Autosomal dominant (500 mg/day, 3 consecutive days for 3 months) and losar- mutations that lead to C3 glomerulonephritis characterized tan (25 mg/day) were added to the therapy. Proteinuria and by glomerular inflammation with complement C3 but not Ig low C3 level did not resolve. Then, eculizumab (900 mg/ or C1q deposits in the kidney have been recently identified week for 4 weeks, 1,200 mg/every 2 weeks thereafter) was [7]. In the original report, the index patient and affected started. After 10-month follow-up, proteinuria (3 g/day) relatives with the disease presented with microscopic with low C3 (20 mg/dl) still continued; however, serum hematuria as well as episodes of macroscopic hematuria albumin had returned to normal (3.3 g/dl) with normal following upper respiratory tract infections, whereas sub- serum creatinine (0.49 mg/dl). sequent studies showed association of CFHR5 mutations Genetic screening detected a novel heterozygous mis- with proteinuria, thus expanding the spectrum [8]. sense variation (c.805T[C; p.Cys269Arg) that was absent Here, we report a pediatric patient with C3G presenting in 180 healthy individuals in gene-encoding CFHR5 with nephrotic syndrome without hematuria that was (Fig. 1d). No mutation was detected in the gene encoding associated with a novel CFHR5 mutation in whom ecu- complement factor H and factor I except for a homozygous lizumab was unsuccessful. known CFI polymorphism (rs11098044). Case report Discussion A 16-year-old girl was admitted to the hospital due to We report an adolescent girl who presented with nephrotic periorbital edema. Her previous and family histories were syndrome and persistently low C3 level associated with an unremarkable. Laboratory parameters were as follows: MPGN pattern in light microscopy of kidney biopsy. We hemoglobin 12.4 g/dl, platelet count 338 9 109/l, white diagnosed C3G given the C3(?)Ig(-) staining pattern in blood cell count 9.600/ll, blood urea nitrogen 8.3 mg/dl immunofluorescence microscopy and further classified the (normal range 5–18 mg/dl), serum creatinine 0.53 mg/dl patient as CFHR5-related nephropathy due to a mutation in (normal range 0.5–0.9 mg/dl), serum albumin 2.69 g/dl CFHR5 [7]. The functional effect of the p.Cys269Arg (normal range 3.2–4.5 g/dl). Serum electrolytes were variation in our patient was evaluated by PolyPhen2 web within normal limits. Serum levels of C3 and C4 were tool with a score result of 1.0 suggesting that this variation 16 mg/dl (normal range 79–152 mg/dl) and 13.3 mg/dl was a damaging one [9]. Cysteine at position 269 is of (normal range 10–40 mg/dl), respectively, with normal critical importance in making a disulfide bond in the ter- plasma levels of complement factors H and I. Urinalysis tiary protein structure; therefore, the cysteine to arginine showed proteinuria (300 mg/dl) with a normal sediment exchange is predicted to be deleterious (http://www.uni and a specific gravity of 1,014. Daily urinary protein prot.org/uniprot/Q9BXR6). Thus, we think that the excretion was 2.086 mg. Renal ultrasonography showed p.Cys269Arg variation is responsible for the phenotype in increased echogenicity in both kidneys. No anti nuclear, our patient. C3G equally affects all ages and both genders anti dsDNA, anti-complement factor H antibodies or C3 and typically presents with hematuria and proteinuria [10]. nephritic factor were detected. A renal biopsy was per- Functional and genetic studies of the alternative comple- formed. Light microscopy showed a membranoprolifera- ment pathway in these disorders have identified heteroge- tive pattern in 14 glomeruli with varying degrees of neous abnormalities. C3 nephritic factors, factor H mesangial matrix increase, segmental endocapillary pro- autoantibodies and mutations in the genes involved in liferation, thickened capillary walls, and double contour regulation of the alternative complement pathway such as formation. Four glomeruli were segmentally or globally CFH and CFI have been demonstrated in patients [10, 11]. sclerosed. The tubulointerstitial area revealed mild fibrosis, We did not detect C3 nephritic factor or anti-complement focal tubular atrophy, a group of foamy histiocytes
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